Pharmacology Lecture 4: Pharmacokinetics II (Principal of Dosing) - Lecture Notes PDF

‫بسم هللا الرحمن الرحيم‬ Lecture 4: Pharmacokinetics II (Principal of dosing) Saif-alnasr Hassan Mohammed Alhassan B. Pharm., M. Pharm., Pharmacology Department of Pharmacology Email: [email protected] Sai...

‫بسم هللا الرحمن الرحيم‬ Lecture 4: Pharmacokinetics II (Principal of dosing) Saif-alnasr Hassan Mohammed Alhassan B. Pharm., M. Pharm., Pharmacology Department of Pharmacology Email: [email protected] Saif-alnasr H. Mohammed 1  Lectures outlines by the end of this lecture students should be able to 1. Describe the clinical importance of PKNs. 2. List and define some important pharmacokinetic parameters. 3. Describe drug kinetic reactions. 4. Define and Describe the dosage regimen. 5. List the aims and methods for prolongation of drug action. 6. List and define doses in pharmacotherapy and drug dose monitoring. Saif-alnasr H. Mohammed 2  Clinical importance of PKNs The objective of drug therapy is to provide plasma concentration within a specific level. The importance: 1. The determination of serum drug levels. 2. The selection of an appropriate dosing regimen (dose and interval between doses). Saif-alnasr H. Mohammed 3 Ideally, the concentration of the drug should be measured at the site of action of the drug At equilibrium, the concentration at receptor site= plasma conc. Plasma concentration depends on: 1) Rate of input (abs). 2) Rate of output (dis/elimination). Saif-alnasr H. Mohammed 4  Concepts MTC MEC Plasma concentration-time curve Saif-alnasr H. Mohammed 5 Therapeutic Window The therapeutic window is the safe range between the minimum therapeutic concentration and the minimum toxic concentration of a drug. Saif-alnasr H. Mohammed 8  Important pharmacokinetic parameters Drug elimination half life (t1/2) It’s a time taken for plasma concentration to fall by one-half. It depends on Vd & Cl. Generally, about 97% of drugs are eliminated after 5 t1/2 Saif-alnasr H. Mohammed 9  Clinical Importance of drug-half life 1. Used to determine the drug plasma concentration at any time. 2. Used to determine the time required to reach plasma SSC. 3. Used to determine the drug elimination time. 4. Dose interval determination. Saif-alnasr H. Mohammed 10  Kinetics of elimination 1.First order elimination  In this kinetic “the rate of elimination is directly proportional to the drug concentration”.  Clearance is constant; that is, the ratio of rate of elimination to plasma concentration is the same regardless of plasma concentration  Constant half life.  No accumulation. Saif-alnasr H. Mohammed 11  Kinetics of elimination 2. Zero order elimination  The rate of elimination remains constant irrespective of drug concentration.  Clearance is not constant.  Accumulation occurs.  Half life is not constant.  Example: ethanol.  N.B: Over dose of some drugs change the kinetics from first order to zero order eg: phenytoin. Saif-alnasr H. Mohammed 12  Kinetics of elimination The elimination of some drugs approaches saturation over the therapeutic range, kinetics changes from first order to zero order at higher doses as occurs in case of phenytoin. Saif-alnasr H. Mohammed 13  Dosage Regimen The manner in which the drug is administered in suitable dose by suitable route with sufficient frequency (dose interval) to suitable duration that ensure maintenance of plasma concentration within therapeutic window for entire period of therapy. Dose: the amount of a medicine (e.g., amount and number). Dose interval: the time between doses (e.g., every 6 hours). Duration of therapy: the time from start drug therapy until the end Saif-alnasr H. Mohammed 14  Example: Mr B, a 72-year-old male patient, who weighs 80 kg and has a serum creatinine concentration of 120mmol/L, is started on a gentamicin dose of 120mg three times daily for 14 days Saif-alnasr H. Mohammed 15  Design and Optimization of Dosage Regimen For successful therapy; the design of an optimal dosage regimen is necessary. This requires to know drug-pharmacokinetic data. Tc = Css How rapidly is achieved and for how long is it maintained? Saif-alnasr H. Mohammed 16  A) Dose and dosing ‘Dose’: is the appropriate amount of a drug needed to produce a certain degree of response in a patient. Includes: Loading dose It’s a large amount of drug administered to the body to rapidly achieved therapeutic concentration.  Loading dose=Vd x Tc N.B: Applied for drugs with large Vd. Saif-alnasr H. Mohammed 17 Maintenance dose :  The dose used to maintain the plasma concentration within a specified range (level) over long periods of therapy. Since at steady state the maintenance rate of drug administration=the rate of elimination then: – Maintenance dose = Css * Cl F  Bolus dose: large single dose given once.  Infusion: is a single dose, continuous, with no intervals. – Infusion rate: Xi = Css * ClT Saif-alnasr H. Mohammed 18  Many factors affect the dose of drugs [through changing the PKN profile at some points]. 1. Variability in drug absorption or metabolism (pharmacogenetic). 2. Physiological differences (age-sex-weights). 3. Disease state and pts condition (e.g. renal & liver disease). 4. Drug –drug interactions. N.B: Subject with renal impairment, Hepatic dysfunction, children and elderly people require special dosage precautions. Saif-alnasr H. Mohammed 19  B) Dose administration Single Repeated administration administration Without (infusion) interval Fixed dose- fixed interval Accumulation until reach steady state Saif-alnasr H. Mohammed 23 The effect of dose interval in concentration fluctuation Saif-alnasr H. Mohammed 27 Patient compliance means strict adherence to the prescribed regimen. How to improve patient compliance?? 🤔 Saif-alnasr H. Mohammed 28 Prolongation of Drug Action Modification of a drug in order to act for a longer period. Advantages: 1. Reduction of administration frequency (more convenient to pt.). 2. Improved patient compliance—a single morning dose is less likely to be forgotten/omitted. 3. Large fluctuations in plasma concentration. 4. Drug effect could be maintained overnight without disturbing sleep, e.g. anti-asthmatics. Saif-alnasr H. Mohammed 29 Drug action can be prolonged by: 1. By prolonging absorption from site of administration as in: a) Oral (sustained release preparation). b) IM and SC (depot formulation). c) Skin (Transdermal drug delivery systems like batches). 2. By increasing plasma protein binding. 3. By retarding rate of metabolism. 4. By retarding renal excretion. Saif-alnasr H. Mohammed 30 Dose in pharmacotherapy Pharmacotherapy is the optimization of drug therapy. According to drugs and conditions are: 1. Standard dose: The same dose is appropriate for most patients. – There is no variation or there is wide TW (penicillin). 2. Regulated dose (antihypertensive). 3. Target level dose (there is a specific conc. is required to be achieved, by measuring plasma concentration (digoxin). Saif-alnasr H. Mohammed 31 4. Titrated dose The dose needed to produce maximal therapeutic effect cannot be given due to intolerable adverse effects.  Low initial dose and upward titration (in most non-critical situations) or high initial dose and downward titration (in critical situations) can be practiced.(eg. anticancer) Saif-alnasr H. Mohammed 32  Drug dose monitoring Drug process should be monitored as: 1. Therapeutic process (↓anginal attack with beta-blockers). 2. Pharmacodynamic process (surrogate markers such as blood glucose with insulin). 3. Pharmacokinetics process (Therapeutic Drug Monitoring “TDM”) TDM: Is a branch of clinical chemistry and clinical pharmacology that specializes in the measurement of drug concentrations in blood. Saif-alnasr H. Mohammed 33  Recommended therapeutic range found in: 1. Medication insert. 2. Books (e.g. Physicians Desk Reference) 3. Articles. Saif-alnasr H. Mohammed 34  Therapeutic drug monitoring (TDM) is particularly useful in the following situations: 1.Drugs with low safety margin—digoxin, anticonvulsants, antiarrhythmics, theophylline, aminoglycoside antibiotics, lithium, tricyclic antidepressants. 2. If individual variations are large—antidepressants, lithium. 3.Potentially toxic drugs used in the presence of renal failure— aminoglycoside antibiotics, vancomycin. 4. In case of poisoning. 5.In case of failure of response without any apparent reason— antimicrobials. 6.To check patient compliance—psychopharmacological agents. Saif-alnasr H. Mohammed 35